In the current funding period, we have discovered that the transcription factor XBP-1, isolated in our laboratory, is required for plasma cell differentiation and antibody production. XBP-1 is the only substrate of IRE1a (IRE1), the ER transmembrane endoribonuclease and kinase that mediates the Unfolded Protein Response (UPR). Our studies have established a link between plasma cell differentiation and the UPR. We have provided evidence that XBP-1 functions to expand the secretory machinery in B cells and acinar cells and is important in dendritic cell survival. Further, XBP-1 is a major target of proteasome inhibitors in the treatment of multiple myeloma. The availability of an XBP-1 flox/flox mouse strain as well as IRE-/- lymphoid chimeras generated in the current funding period will allow us to explore many unanswered questions about the function of IRE1, XBP-1 and the UPR in pre B (IRE1) and plasma cell (XBP-1) differentiation, in normal and malignant dendritic cell survival and function, in autoimmune disease and in multiple myeloma. In the next funding period we propose to 1) Further explore the role of XBP-1 in B cell commitment.2) Identify novel components of the IRE1 signaling pathway. 3) Investigate the function of XBP-1 and the UPR in normal and malignant dendritic cells (DCs). 4) Examine the role of XBP-1 in autoimmune disease.5) Investigate the requirement of XBP-1 for the development and propagation of plasma cell neoplasms.